Apte Anisha, Dutta Dey Pujarini, Julakanti Srisaianirudh Reddy, Midura-Kiela Monica, Skopp Stacy M, Canchis Jimena, Fauser Tobias, Bardill James, Seal Sudipta, Jackson David M, Ghishan Fayez K, Kiela Pawel R, Zgheib Carlos, Liechty Kenneth W
Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children's at Diamond Children's Medical Center, 1656 E Mabel St, Rm 230, Tucson, AZ 85721, USA.
Department of Pediatrics, Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, AZ 85621, USA.
Pharmaceutics. 2024 Dec 9;16(12):1573. doi: 10.3390/pharmaceutics16121573.
Dysregulated inflammation and oxidative stress are strongly implicated in the pathogenesis of inflammatory bowel disease. We have developed a novel therapeutic that targets inflammation and oxidative stress. It is comprised of microRNA-146a (miR146a)-loaded cerium oxide nanoparticles (CNPs) (CNP-miR146a). We hypothesized that oral delivery of CNP-miR146a would reduce colonic inflammation in a mouse model of established, chronic, T cell-mediated colitis. The stability of CNP-miR146a and mucosal delivery was assessed in vitro with simulated gastrointestinal fluid and in vivo after oral gavage by quantitative real-time RT-PCR. The efficacy of orally administered CNP-miR146a was tested in mice with established colitis using the model of adoptive naïve T-cell transfer in recombinant activating gene 2 knockout (Rag2) mice. Measured outcomes included histopathology; CD45 immune cell infiltration; oxidative DNA damage (tissue 8-hydroxy-2'-deoxyguanosine; 8-OHdG); expression of IL-6 and TNF mRNA and protein, and flow cytometry analysis of lamina propria Th1 and Th17 cell populations. miR146a expression remained stable in simulated gastric and intestinal conditions. miR146a expression increased in the intestines of mice six hours following oral gavage of CNP-miR146a. Oral delivery of CNP-miR146a in mice with colitis was associated with reduced inflammation and oxidative stress in the proximal and distal colons as evidenced by histopathology scoring, reduced immune cell infiltration, reduced IL-6 and TNF expression, and decreased populations of CD4TbetIFNg+ Th1, CD4RorgTIL17 Th17, as well as pathogenic double positive IFNgIL17 T cells. : CNP-miR146a represents a novel orally available therapeutic with high potential to advance into clinical trials.
炎症调节异常和氧化应激与炎症性肠病的发病机制密切相关。我们开发了一种针对炎症和氧化应激的新型疗法。它由负载微小RNA-146a（miR146a）的氧化铈纳米颗粒（CNPs）（CNP-miR146a）组成。我们假设口服CNP-miR146a可减轻已建立的慢性T细胞介导的结肠炎小鼠模型中的结肠炎症。通过定量实时RT-PCR在体外模拟胃肠液中评估CNP-miR146a的稳定性和黏膜递送情况，并在口服灌胃后在体内进行评估。使用重组激活基因2敲除（Rag2）小鼠的过继性幼稚T细胞转移模型，在患有结肠炎的小鼠中测试口服CNP-miR146a的疗效。测量的结果包括组织病理学；CD45免疫细胞浸润；氧化性DNA损伤（组织8-羟基-2'-脱氧鸟苷；8-OHdG）；IL-6和TNF mRNA及蛋白的表达，以及对固有层Th1和Th17细胞群体的流式细胞术分析。miR146a表达在模拟的胃和肠条件下保持稳定。口服CNP-miR146a后6小时，小鼠肠道中miR146a表达增加。通过组织病理学评分、免疫细胞浸润减少、IL-6和TNF表达降低以及CD4TbetIFNg+ Th1、CD4RorgTIL17 Th17以及致病性双阳性IFNgIL17 T细胞群体减少证明，在患有结肠炎的小鼠中口服CNP-miR146a与近端和远端结肠炎症和氧化应激减轻有关。CNP-miR146a代表一种具有很高潜力推进到临床试验的新型口服可用疗法。
